Journal Article

Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders

Geschwind, Daniel H., Gandal, Michael J., Parikshak, Neelroop N.

2015

Overview

Key Points When applying high-throughput molecular methods to the study of neurodevelopmental disorders, major challenges include the spatial and temporal heterogeneity of the brain, a lack of appropriate tissue available for studies and poorly defined phenotypes. Transcriptomics assays are currently the most widely used functional genomic assays in neurobiology owing to their ability to efficiently capture tissue-specific spatial and temporal heterogeneity in a high-throughput manner. Principles from transcriptomic studies will aid in evaluating additional molecular and cellular levels of regulation. We review the principles of network analysis and describe how gene networks provide a framework to organize, integrate and analyse large-scale genomic data sets in neurobiology. We review representative differential expression and gene network studies in neurodevelopmental disorders and neurodegenerative diseases and identify some next steps in data generation and integration that are necessary for progress in the field. We provide guidelines for designing, analysing and evaluating high-throughput transcriptomic studies in the brain in order to improve study quality and reproducibility. The study of the genetic basis of neurodevelopmental disorders and neurodegenerative diseases has progressed through recent large-scale association studies as well as the application of a range of high-throughput molecular methods. In this Review, the authors examine systems biology approaches and demonstrate how gene networks provide an organizing framework to integrate the analysis of large-scale genetic and molecular profiling data sets to characterize the genetic basis of phenotypes that affect the central nervous system. Genetic and genomic approaches have implicated hundreds of genetic loci in neurodevelopmental disorders and neurodegeneration, but mechanistic understanding continues to lag behind the pace of gene discovery. Understanding the role of specific genetic variants in the brain involves dissecting a functional hierarchy that encompasses molecular pathways, diverse cell types, neural circuits and, ultimately, cognition and behaviour. With a focus on transcriptomics, this Review discusses how high-throughput molecular, integrative and network approaches inform disease biology by placing human genetics in a molecular systems and neurobiological context. We provide a framework for interpreting network biology studies and leveraging big genomics data sets in neurobiology.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/114/2114 / 631/208/2489/144 / 631/208/366 / 631/378/1689 / 631/378/2583 / Aging / Agriculture / Animal Genetics and Genomics / Biology / Biomedicine / Brain - cytology / Brain - metabolism / Brain research / Cancer Research / Cognition & reasoning / Developmental Disabilities - genetics / Disease / Epigenetics / Gene Expression Profiling - methods / Gene Function / Gene loci / Gene Regulatory Networks - genetics / Genetic aspects / Genetics / High-Throughput Screening Assays - methods / High-Throughput Screening Assays - trends / Human Genetics / Humans / Models, Neurological / Nervous system / Nervous system diseases / Neurobiology / Neurobiology - methods / Neurobiology - trends / Neurodegeneration / Neurodegenerative Diseases - genetics / Neurophysiology / Neurosciences / review-article / Systems biology / Systems Biology - methods / Systems Biology - trends